Radiation Therapy has played a major role in cancer therapeutics since its discovery more than one hundred years ago. It is estimated that in the United States and Europe more than one million individuals receive radiation therapy every year as part of their cancer treatment. Radiation therapy can be curative, particularly in prostate cancer, head and neck cancer and cervical cancer where cure rates with definitive radiation therapy are comparable with those achieved with radical surgery. It also plays an important role in multi-modality organ conservation protocols as in breast cancer, rectal cancer, soft tissue sarcoma and laryngeal cancer where cure rates have been equaled to those achieved with radical surgery with the advantage of organ function preservation.
In the last decade a significant improvement in the cure rates and overall survival of cervical, head and neck and lung cancer has been achieved by delivering concurrent radiotherapy and chemotherapy (radiochemotherapy). Phase III prospective randomized trials have shown concurrent radiochemotherapy improves overall survival over standard radiotherapy in cervical, head and neck, esophageal and lung cancer. In general the beneficial effect of concurrent radiochemotherapy has been ascribed to the radiosensitization effect induced by chemotherapy, which makes both normal and malignant cells more sensitive to radiation-induced damage. Interestingly, most drugs used in these trials have not been developed as “radiosensitizers” but have been discovered to radiosensitize after they have been tested in the clinic as cancer toxic agents. Therefore the development of targeted radiosensitizing drugs is an attractive area of research with significant clinical potential.
A major hurdle to the development of better radiosensitizing drugs has been the limited number of known potential targets. In the last decade significant advances in our molecular understanding of radiation response has led to the development of several promising targeted radiosensitizers, some of which are currently undergoing clinical evaluation. The radiation signaling pathways addressed by these radiosensitizers include: Ras/PI3K/Akt which may be activated directly by tyrosine kinases or receptor-activated Ras, DNA repair (DNA-PK, PARP-1), cyclooxygenase-2 (COX-2), toposimorease-I, Epidermal Growth Factor (EGF) and others. However it is very likely that the number of unknown molecular pathways/targets involved in radiation response outnumber the number of known targets. With the advent of the functional genomics era, it is hoped that technologies may be developed that may allow us to identify potential targets using a genomic approach.